Process for preparing imidazoquinolinamines

ABSTRACT

A process for preparing 1H-imidazo[4,5-c]quinolin-4-amines is disclosed. The process involves reacting a 6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline with triphenylphosphine and hydrolyzing the product thereof.

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates to processes for preparing1H-imidazo[4,5-c]quinolin-4-amines and to intermediates for use inpreparing 1H-imidazo[4,5-c]quinolin-4-amines.

2. Description of the Related Art

Certain antiviral immunomodulator 1H-imidazo[4,5-c]quinolin-4-amines andmethods for their preparation are known and disclosed. For example U.S.Pat. Nos. 4,689,338 and 4,929,624 (Gerster) disclose a method involvingthe step of heating the corresponding 4-chloro compound in the presenceof ammonium hydroxide or ammonia under pressure to provide the 4-aminocompound. U.S. Pat. No. 4,988,815 (Andre) discloses a process involvingamination of the 4-position of a 3-nitro-1,4-dichloroquinoline. Thisprocess too involves as a final step the reaction of ammonia with a4-chloro-1H-imidazo[4,5-c]quinoline.

Milder methods have been used in order to introduce the 4-amino group of1H-imidazo[4,5-c]quinolin-4-amines. U.S. Pat. No. 5,175,296 (Gerster)discloses a process involving the reaction of a1H-imidazo[4,5-c]quinoline 5N-oxide with an organic isocyanate andhydrolyzing the product to provide the 4-amino compound. U.S. Pat. No.5,367,076 (Gerster) discloses a process involving the reaction of a1H-imidazo[4,5-c]quinoline 5N-oxide with an acylating agent and reactingthe product with an aminating agent to provide the 4-amino compound.U.S. Pat. No. 5,395,937 (Nikolaides) discloses a process involvingamination of the 4-position of a 3-nitroquinoline-2,4-disulfonate with asubstituted amine. The final step of the process involves hydrogenolysisto provide the 4-amino compound.

SUMMARY OF THE INVENTION

This invention provides a process for preparing a1H-imidazo[4,5-c]quinolin-4-amine comprising the steps of:

-   -   (i) providing a tetrazolo[1,5-a]quinolin-5-ol;    -   (ii) nitrating the compound from step (i) to provide a        4-nitrotetrazolo[1,5-a]quinolin-5-ol;    -   (iii) sulfonylating the compound from step (ii) to provide a        4-nitrotetrazolo[1,5-a]quinolin-5-sulfonate;    -   (iv) reacting the compound from step (iii) with an amine to        provide a        (5-substituted)-4-nitrotetrazolo[1,5-a]quinolin-5-amine;    -   (v) reducing the compound from step (iv) to provide a        (5-substituted)tetrazolo[1,5-a]quinolin-4,5-diamine;    -   (vi) reacting the compound from step (v) with a carboxylic acid        or an equivalent thereof to provide a (5-substituted)        (6-substituted) 6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline;    -   (vii) reacting the compound from step (vi) with        triphenylphosphine to provide a (1-substituted) (2-substituted)        N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine;    -   (viii) hydrolyzing the compound from step (vii) to provide a        (1-substituted) (2-substituted)        1H-imidazo[4,5-c]quinolin-4-amine; and    -   (xi) isolating the (1-substituted) (2-substituted)        1H-imidazo[4,5-c]quinolin-4-amine or a pharmaceutically        acceptable addition salt thereof.

This invention also provides a process for preparing a1H-imidazo[4,5-c]quinolin-4-amine comprising the steps of:

-   -   (i) providing a (4-substituted) amino-2-chloro-3-nitroquinoline;    -   (ii) reacting the compound from step (i) with sodium azide to        provide (5-substituted)-4-nitrotetrazolo[1,5-a]quinolin-5-amine;    -   (iii) reducing the compound from step (ii) to provide a        (5-substituted)tetrazolo[1,5-a]quinolin-4,5-diamine;    -   (iv) reacting the compound from step (iii) with a carboxylic        acid or an equivalent thereof to provide a (5-substituted)        (6-substituted) 6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline;    -   (v) reacting the compound from step (iv) with triphenylphosphine        to provide a (1-substituted) (2-substituted)        N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine;    -   (vi) hydrolyzing the compound from step (v) to provide a        (1-substituted) (2-substituted)        1H-imidazo[4,5-c]quinolin-4-amine; and    -   (vii) isolating the (1-substituted) (2-substituted)        1H-imidazo[4,5-c]quinolin-4-amine or a pharmaceutically        acceptable addition salt thereof. This invention also provides a        process for preparing a 1H-imidazo[4,5-c]quinolin-4-amine        comprising the steps of:    -   (i) providing a (1-substituted) (2-substituted)        4-chloro-1H-imidazo[4,5-c]quinoline;    -   (ii) reacting the compound from step (i) with hydrazine to        provide a (1-substituted) (2-substituted)        4-hydrazino-1H-imidazo[4,5-c]quinoline;    -   (iii) reacting the compound from step (ii) with sodium nitrite        to provide a (5-substituted) (6-substituted)        6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline;    -   (iv) reacting the compound from step (iii) with        triphenylphosphine to provide a (1-substituted) (2-substituted)        N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine;    -   (v) hydrolyzing the compound from step (iv) to provide a        (1-substituted) (2-substituted)        1H-imidazo[4,5-c]quinolin-4-amine; and    -   (vi) isolating the (1-substituted) (2-substituted)        1H-imidazo[4,5-c]quinolin-4-amine or a pharmaceutically        acceptable addition salt thereof.

This invention also provides processes involving certain of the variousindividual steps set forth above, and combinations of such steps.

In another aspect this invention also provides4-nitrotetrazolo[1,5-a]quinolin-5-ols,4-nitrotetrazolo[1,5-a]quinoline-5-sulfonates,(5-substituted)-4-nitrotetrazolo [1,5-a]quinolin-5-amines,(5-substituted)tetrazolo[1,5-a]quinolin-4,5-diamines, (5-substituted)(6-substituted) 6H-imidazo[4,5-c]tetrazolo[1,5-a]quinolines,(1-substituted) (2-substituted) 4-hydrazino-1H-imidazo[4,5-c]quinolines,and (1-substituted) (2-substituted)N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amines.

DETAILED DESCRIPTION OF THE INVENTION

Substituents designated parenthetically herein indicate that thesubstituent is optionally present, e.g., a 4-(substituted) aminocompound contains either an unsubstituted 4-amino group or a substituted4-amino group.

Reaction Scheme I illustrates processes of the invention and thepreparation of compounds of the invention. The unsubstituted compound ofFormula I is a known compound and other compounds of Formula I can beprepared by methods known to those skilled in the art and disclosed,e.g., in Chemistry of Heterocyclic Compounds (English Edition), 1981,16, (12), 1286-1288 (Zyryanov).

In step (1) of Reaction Scheme I a 4-nitrotetrazolo[1,5-a]quinolin-5-olof Formula II is provided by nitrating a tetrazolo[1,5-a]quinolin-5-olof Formula I. Conventional conditions for such reactions are well known.Preferred conditions in the instance where R is hydrogen involve heatingin acetic acid in the presence of nitric acid. Preferred conditions inother instances will depend upon the particulartetrazolo[1,5-a]quinolin-5-ol used, and those skilled in the art will beable to select suitable conditions. The product can be isolated from thereaction mixture using conventional methods.

In step (2) of Reaction Scheme I a4-nitrotetraozolo[1,5-a]quinolin-5-sulfonate of Formula III is providedby reacting a 4-nitrotetrazolo[1,5-a]quinolin-5-ol of Formula II with asulfonyl halide or preferably a sulfonic anhydride. Suitable sulfonylhalides include alkylsulfonyl halides such as methanesulfonyl chlorideand trifluoromethanesulfonyl chloride, and arylsulfonyl halides such asbenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride andp-toluenesulfonyl chloride. Suitable sulfonic anhydrides include thosecorresponding to the above-mentioned sulfonyl halides. Sulfonicanhydrides are preferred in view of the fact that the sulfonate aniongenerated as a by-product of the reaction is a relatively poornucleophile and as such does not give rise to undesired side productssuch as those in which the nitro group is displaced. A particularlypreferred sulfonic anhydride is trifluoromethanesulfonic anhydride.

The reaction is preferably carried out by combining a compound ofFormula II with a base, preferably an excess of a tertiary amine base(e.g., a trialkylamine base such as triethyl amine) in a suitablesolvent such as dichloromethane and then adding the sulfonyl halide orsulfonic anhydride. The addition is preferably carried out in acontrolled fashion (e.g., dropwise) and at a reduced temperature (e.g.,about 0° C.). The product can be isolated by conventional methods or itcan be carried on without isolation as described below in connectionwith step (3).

In step (3) of Reaction Scheme I a (5-substituted)4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula IV is provided byreacting a 4-nitrotetrazolo[1,5-a]quinolin-5-sulfonate of Formula IIIwith an amine, preferably in the presence of an excess of an amine basein a solvent such as dichloromethane. Suitable amines include ammoniaand preferably primary amines. Primary amines provide 5-substitutedamino compounds of Formula IV wherein the amino substituent isrepresented by R₁. Particularly preferred amines include isobutylamineand 2-aminomethyl-2-propanol.

The reaction can be carried out by adding an excess of amine to thereaction mixture resulting from Step (2). The reaction can also becarried out by adding an excess of amine to a solution of the compoundof Formula III in a solvent such as dichloromethane. As the sulfonate isa relatively facile leaving group the reaction can be run at ambienttemperature. The product can be isolated from the reaction mixture usingconventional methods.

In step (4) of Reaction Scheme I a(5-substituted)tetrazolo[1,5-a]quinolin-4,5-diamine of Formula V isprovided by reducing a (5-substituted)4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula IV. Methods for suchreduction are well know to those skilled in the art. Preferably thereduction is carried out using a conventional heterogeneoushydrogenation catalyst such as platinum on carbon or palladium oncarbon. The reduction can be conveniently carried out on a Paarapparatus in a solvent such as ethanol. The product can be isolated fromthe reaction mixture using conventional methods.

In step (5) of Reaction Scheme I a (5-substituted) (6-substituted)6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline of Formula VI is provided byreacting a (5-substituted)tetrazolo[1,5-a]quinolin-4,5-diamine ofFormula V with a carboxylic acid or an equivalent thereof. Suitableequivalents to carboxylic acid include acid halides, orthoesters, and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will give rise to the desired 6-substituent in thecompound of Formula VI wherein the 6-substituent is designated R₂ (e.g.,acetyl chloride will give rise to a compound where R₂ is methyl). Thereaction can be run in the absence of solvent or preferably in an inertsolvent in the presence of a carboxylic acid or equivalent thereof withsufficient heating to drive off any alcohol or water formed as a sideproduct of the reaction. The product can be isolated from the reactionmixture using conventional methods.

In step (6) of Reaction Scheme I a (1-substituted) (2-substituted)N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine of Formula VIIis provided by reacting a (5-substituted) (6-substituted)6H-imidazo[4,5-c]tetrazolo[1,5-]quinoline of Formula VI withtriphenylphosphine. The reaction can be carried out by combining acompound of Formula VI with triphenylphosphine in a suitable solventsuch as 1,2-dichlorobenzene and heating. The product can be isolatedfrom the reaction mixture using conventional methods.

In step (7) of Reaction Scheme I a (1-substituted) (2-substituted)1H-imidazo[4,5-c]quinoline-4-amine of Formula VIII is provided byhydrolysis of a (1-substituted) (2-substituted)N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine of Formula VII.Such a reaction can be carried out by general methods well known tothose skilled in the art (e.g., by heating in a lower alkanol in thepresence of an acid). The product can be isolated from the reactionmixture by conventional means.

In Reaction Scheme I, R′ can be any group that can be incorporated intoa sulfonyl halide or a sulfonic anhydride. Alkyl (e.g., methyl),haloalkyl including perfluoroalkyl (e.g., trifluoromethyl) and aryl(e.g., phenyl, halophenyl and tolyl) are all suitable.

Reaction Scheme II illustrates processes of the invention and thepreparation of compounds of the invention. Compounds of Formula IX andmethods for their preparation are known and disclosed, e.g. in U.S. Pat.No. 4,988,815 (Andre), and U.S. Pat. No. 5,268,376 (Gerster), bothpatents being incorporated herein by reference.

In step (1) of Reaction Scheme II a (5-substituted)4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula IV is provided byreacting a (4-substituted) amino-2-chloro-3-nitroquinoline of Formula IXwith sodium azide. The reaction can be carried out by combining thecompound of Formula IX with sodium azide in a suitable solvent such asN,N-dimethylformamide and heating (about 50° C.). The product can beisolated from the reaction mixture using conventional methods.

Steps (2), (3), (4) and (5) of Reaction Scheme II can be carried out inthe same manner as steps (4), (5), (6) and (7) of Reaction Scheme Irespectively.

Reaction Scheme III illustrates processes of the invention and thepreparation of compounds of the invention. Compounds of Formula X andmethods for their preparation are known and disclosed, e.g., in EuropeanPatent Application 90.301776.3, U.S. Pat. No. 4,689,338 (Gerster), U.S.Pat. No. 4,698,348 (Gerster), U.S. Pat. No. 4,929,625 (Gerster), U.S.Pat. No. 4,988,815 (Andre), U.S. Pat. No. 5,268,376 (Gerster), and U.S.Pat. No. 5,389,640 (Gerster) all six patents being incorporated hereinby reference.

In step (1) of Reaction Scheme III a (1-substituted) (2-substituted)4-hydrazino-1H-imidazo[4,5-c]quinoline of Formula XI is provided byreacting a (1-substituted) (2-substituted)4-chloro-1H-imidazo[4,5-c]quinoline of Formula X with hydrazine. Thereaction can be carried out by combining a compound of Formula X with anexcess of hydrazine and heating if necessary. The product can beisolated from the reaction mixture using conventional methods.

In step (2) of Reaction Scheme III a (5-substituted) (6-substituted)6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline of Formula VI is provided byreacting a (1-substituted) (2-substituted)4-hydrazino-1H-imidazo[4,5-c]quinoline of Formula XI with sodiumnitrite. The reaction can be carried out by combining the compound ofFormula XI with sodium nitrite in a suitable solvent (e.g., water) inthe presence of an acid (e.g., acetic acid). The product can be isolatedfrom the reaction mixture using conventional methods.

Steps (3) and (4) of Reaction Scheme III can be carried out in the samemanner as steps (6) and (7) of Reaction Scheme I respectively.

The compounds of Formula VIII can be used in the form of acid additionsalts such as hydrochlorides, dihydrogen sulfates, trihydrogenphosphates, hydrogen nitrates, methane sulfonates and salts of otherpharmaceutically acceptable acids. Pharmaceutically acceptable acidaddition salts of Formula VIII are generally prepared by reaction of therespective compound with an equimolar amount of a strong acid,preferably an inorganic acid such as hydrochloric, sulfuric orphosphoric acid or an organic acid such as methanesulfonic acid in apolar solvent. Isolation of the salt is facilitated by the addition of asolvent in which the salt is insoluble (e.g., diethyl ether).

Processes of the invention provide as a final product a1H-imidazo[4,5-c]quinolin-4-amine, preferred embodiments of which can berepresented by Formula VIII.

Preferably the 1H-imidazo[4,5-c]quinolin-4-amine is a compound definedby one of Formulas XXI-XXV below:

wherein

-   -   R₁₁ is selected from the group consisting of alkyl,        hydroxyalkyl, acyloxyalkyl, benzyl, (phenyl)ethyl and phenyl,        said benzyl, (phenyl)ethyl or phenyl substituent being        optionally substituted on the benzene ring by one or two        moieties independently selected from the group consisting of        alkyl of one to about four carbon atoms, alkoxy of one to about        four carbon atoms and halogen, with the proviso that if said        benzene ring is substituted by two of said moieties, then said        moieties together contain no more than 6 carbon atoms;        acylaminoalkyl wherein the alkyl moiety contains two to four        carbon atoms; disubstituted aminoalkyl wherein the alkyl moiety        contains two to four carbon atoms; morpholinoalkyl wherein the        alkyl moiety contains two to four carbon atoms; R₂₁ is selected        from the group consisting of hydrogen, alkyl of one to about        eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the        benzyl, (phenyl)ethyl or phenyl substituent being optionally        substituted on the benzene ring by one or two moieties        independently selected from the group consisting of alkyl of one        to about four carbon atoms, alkoxy of one to about four carbon        atoms and halogen, with the proviso that when the benzene ring        is substituted by two of said moieties, then the moieties        together contain no more than 6 carbon atoms; and each R_(A) is        independently selected from the group consisting of alkoxy of        one to about four carbon atoms, halogen and alkyl of one to        about four carbon atoms, and n is an integer from 0 to 2, with        the proviso that if n is 2, then said R_(A) groups together        contain no more than 6 carbon atoms;        wherein    -   R₁₂ is selected from the group consisting of straight chain or        branched chain alkenyl containing 2 to about 10 carbon atoms and        substituted straight chain or branched chain alkenyl containing        2 to about 10 carbon atoms, wherein the substituent is selected        from the group consisting of straight chain or branched chain        alkyl containing 1 to about 4 carbon atoms and cycloalkyl        containing 3 to about 6 carbon atoms; and cycloalkyl containing        3 to about 6 carbon atoms substituted by straight chain or        branched chain alkyl containing 1 to about 4 carbon atoms; and    -   R₂₂ is selected from the group consisting of hydrogen, straight        chain or branched chain alkyl containing one to about eight        carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl,        (phenyl)ethyl or phenyl substituent being optionally substituted        on the benzene ring by one or two moieties independently        selected from the group consisting of straight chain or branched        chain alkyl containing one to about four carbon atoms, straight        chain or branched chain alkoxy containing one to about four        carbon atoms, and halogen, with the proviso that when the        benzene ring is substituted by two such moieties, then the        moieties together contain no more than 6 carbon atoms; and    -   each R_(B) is independently selected from the group consisting        of straight chain or branched chain alkoxy containing one to        about four carbon atoms, halogen, and straight chain or branched        chain alkyl containing one to about four carbon atoms, and n is        an integer from zero to 2, with the proviso that if n is 2, then        said R_(B) groups together contain no more than 6 carbon atoms;        wherein    -   R₂₃ is selected from the group consisting of hydrogen, straight        chain or branched chain alkyl of one to about eight carbon        atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl,        (phenyl)ethyl or phenyl substituent being optionally substituted        on the benzene ring by one or two moieties independently        selected from the group consisting of straight chain or branched        chain alkyl of one to about four carbon atoms, straight chain or        branched chain alkoxy of one to about four carbon atoms, and        halogen, with the proviso that when the benzene ring is        substituted by two such moieties, then the moieties together        contain no more than 6 carbon atoms; and    -   each R_(C) is independently selected from the group consisting        of straight chain or branched chain alkoxy of one to about four        carbon atoms, halogen, and straight chain or branched chain        alkyl of one to about four carbon atoms, and n is an integer        from zero to 2, with the proviso that if n is 2, then said R_(C)        groups together contain no more than 6 carbon atoms;        wherein R₁₄ is —CHR_(x)R_(y)        wherein    -   R_(y) is hydrogen or a carbon-carbon bond, with the proviso that        when R_(y) is hydrogen R_(x) is alkoxy of one to about four        carbon atoms, hydroxyalkoxy of one to about four carbon atoms,        1-alkynyl of two to about ten carbon atoms, tetrahydropyranyl,        alkoxyalkyl wherein the alkoxy moiety contains one to about four        carbon atoms and the alkyl moiety contains one to about four        carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso        that when R_(y) is a carbon-carbon bond R_(y) and R_(x) together        form a tetrahydrofuranyl group optionally substituted with one        or more substituents independently selected from the group        consisting of hydroxy and hydroxyalkyl of one to about four        carbon atoms;    -   R₂₄ is selected from the group consisting of hydrogen, alkyl of        one to about four carbon atoms, phenyl, and substituted phenyl        wherein the substituent is selected from the group consisting of        alkyl of one to about four carbon atoms, alkoxy of one to about        four carbon atoms, and halogen; and    -   R_(D) is selected from the group consisting of hydrogen,        straight chain or branched chain alkoxy containing one to about        four carbon atoms, halogen, and straight chain or branched chain        alkyl containing one to about four carbon atoms;        wherein    -   R₁₅ is selected from the group consisting of: hydrogen; straight        chain or branched chain alkyl containing one to about ten carbon        atoms and substituted straight chain or branched chain alkyl        containing one to about ten carbon atoms, wherein the        substituent is selected from the group consisting of cycloalkyl        containing three to about six carbon atoms and cycloalkyl        containing three to about six carbon atoms substituted by        straight chain or branched chain alkyl containing one to about        four carbon atoms; straight chain or branched chain alkenyl        containing two to about ten carbon atoms and substituted        straight chain or branched chain alkenyl containing two to about        ten carbon atoms, wherein the substituent is selected from the        group consisting of cycloalkyl containing three to about six        carbon atoms and cycloalkyl containing three to about six carbon        atoms substituted by straight chain or branched chain alkyl        containing one to about four carbon atoms; hydroxyalkyl of one        to about six carbon atoms; alkoxyalkyl wherein the alkoxy moiety        contains one to about four carbon atoms and the alkyl moiety        contains one to about six carbon atoms; acyloxyalkyl wherein the        acyloxy moiety is alkanoyloxy of two to about four carbon atoms        or benzoyloxy, and the alkyl moiety contains one to about six        carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl,        (phenyl)ethyl or phenyl substituent being optionally substituted        on the benzene ring by one or two moieties independently        selected from the group consisting of alkyl of one to about four        carbon atoms, alkoxy of one to about four carbon atoms, and        halogen, with the proviso that when said benzene ring is        substituted by two of said moieties, then the moieties together        contain no more than six carbon atoms; acylaminoalkyl wherein        the alkyl moiety contains two to four carbon atoms;        disubstituted aminoalkyl wherein the alkyl moiety contains two        to four carbon atoms; morpholinoalkyl wherein the alkyl moiety        contains two to four carbon atoms;    -   R₂₅ is        wherein    -   R_(S) and R_(T) are independently selected from the group        consisting of hydrogen, alkyl of one to about four carbon atoms,        phenyl, and substituted phenyl wherein the substituent is        selected from the group consisting of alkyl of one to about four        carbon atoms, alkoxy of one to about four carbon atoms, and        halogen;    -   X is selected from the group consisting of alkoxy containing one        to about four carbon atoms, alkoxyalkyl wherein the alkoxy        moiety contains one to about four carbon atoms and the alkyl        moiety contains one to about four carbon atoms, haloalkyl of one        to about four carbon atoms, alkylamido wherein the alkyl group        contains one to about four carbon atoms, amino, substituted        amino wherein the substituent is alkyl or hydroxyalkyl of one to        about four carbon atoms, azido, alkylthio of one to about four        carbon atoms; and    -   R_(E) is selected from the group consisting of hydrogen,        straight chain or branched chain alkoxy containing one to about        four carbon atoms, halogen, and straight chain or branched chain        alkyl containing one to about four carbon atoms;    -   or a pharmaceutically acceptable salt of any of the foregoing.

The compounds recited above are disclosed and claimed in the severalpatents noted above in the Summary of the Invention and discussed below.

In instances where n can be zero, one, or two, n is preferably zero orone.

The substituents R_(A)-R_(E) above are species embraced by R. Thepreferred R substituent is hydrogen.

The substituents R₁₁-R₁₅ above are species embraced by R₁. The preferredR₁ substituents are alkyl of one to about six carbon atoms, hydroxyalkyl wherein the alkyl moiety contains one to about 6 carbon atoms, andarylalkyl wherein the alkyl moiety contains one to about three carbonatoms. Most preferably the R₁ substituent is 2-methylpropyl,2-hydroxy-2-methylpropyl, benzyl or phenylethyl.

The substituents R₂₁-R₂₅ above are species embraced by R₂ The preferredR₂ substituents are hydrogen, alkyl of one to about four carbon atoms,alkoxyalkyl wherein the alkoxy moiety contains one to about four carbonatoms and the alkyl moiety contains one to about four carbon atoms,hydroxyl alkyl wherein the alkyl moiety contains one to about fourcarbon atoms, haloalkyl wherein the alkyl moiety contains one to aboutfour carbon atoms, and aryloxymethyl. Most preferably the R₂ substituentis hydrogen, methyl, ethoxymethyl, or benzyl.

Certain R substituents, R₁ substituents, and R₂ substituents will beincompatible with the particular reaction conditions described above inconnection with the Reaction Schemes. Those skilled in the art, however,will be able to select alternative conditions under which the severalsteps can be carried out and/or methods of functional group protectionand manipulation that will allow the use of the processes of theinvention in the preparation of 1H-imidazo[4,5-c]quinolin-4-amines ofdiverse structures.

Certain 1H-imidazo[4,5-c]quinolin-4-amines have been disclosed asantiviral agents (see, e.g., European Patent Application 90.301776.3(Gerster), U.S. Pat. No. 4,689,338 (Gerster), U.S. Pat. No. 4,929,624(Gerster), U.S. Pat. No. 5,266,575 (Gerster), U.S. Pat. No. 5,268,376(Gerster), and U.S. Pat. No. 5,389,640 (Gerster) all five patentsincorporated herein by reference). Certain of these compounds are alsoknown to induce biosynthesis of cytokines such as interferons,interleukins, and tumor necrosis factor in humans and in mice.

The Examples below are intended to illustrate the invention. All partsand percentages are by weight unless otherwise indicated.

EXAMPLE 1 Tetrazolo[1,5-a]quinolin-5-ol

Part A

Anthranilic acid (274.3 g) and acetic anhydride (1.1 L) were combinedthen heated at reflux for 3.5 hours. The reaction mixture wasconcentrated under vacuum. The residue was combined with methanol (550mL) then concentrated under vacuum to provide2-methyl-4-oxo-3,1-benzoxazine as a brown oil.

Part B

The crude 2-methyl-4-oxo-3,1-benzoxazine was dissolved in acetic acid(1.9 L). Sodium azide (130.0 g) was added to the solution in portionswith stirring. The reaction mixture was cooled in an ice bath tomaintain the reaction temperature at 25 to 30° C. during the addition.The reaction mixture was allowed to stir at ambient temperature over theweekend. The acetic acid was removed under vacuum to provide a whitesolid. The solid was combined with 10% sodium hydroxide (1.4 L) thenheated on a steam bath for 1 hour. Additional sodium hydroxide (120 g of50% sodium hydroxide) was added. The mixture was heated on a steam bathfor an additional hour then allowed to cool to ambient temperatureovernight. Additional sodium hydroxide (120 g of 50% sodium hydroxide)was added. The mixture was heated on a steam bath for 2 hours thenallowed to cool. The reaction mixture was poured with rapid stirringinto a mixture of concentrated hydrochloric acid (1.0 L) and ice (3 L).The resulting mixture was stirred at ambient temperature overnight. Aprecipitate was isolated by filtration, rinsed with water then slurriedwith water (4 L). The solid was isolated by filtration, rinsed withwater then oven dried at 50° C. to provide 278.0 g of crude2-(5-methyl-1H-tetrazol-1-yl)benzoic acid as a tan solid, m.p. 157-160°C. The crude material was dissolved in 10% sodium hydroxide (2.5 L). Theresulting solution was heated (95-99° C.) for 2.5 hours, cooled, thenpoured with vigorous stirring into a mixture of concentratedhydrochloric acid (500 mL) and ice (5 L). The resulting mixture wasallowed to stir for 2 hours. The precipitate was isolated by filtration,rinsed with water, then slurried with water (3 L). The solid wasisolated by filtration, rinsed with water then dried overnight atambient temperature to provide 228 g of2-(5-methyl-1H-tetrazol-1-yl)benzoic acid, m.p. 164-166° C.

Part C

Acetone (3.2 L) and 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (228 g)were combined then stirred at ambient temperature for 15 minutes.Potassium carbonate (228 g) was added to the reaction mixture in asingle portion. Iodoethane (366.8 g) was added dropwise to the reactionmixture producing a slight exotherm. The reaction mixture was heated atreflux for about 4 hours then stirred overnight while cooling to ambienttemperature. The precipitated salts were removed by filtration thenrinsed with acetone. The combined filtrates were evaporated undervacuum. The residue was dissolved in dichloromethane (1.5 L). Thedichloromethane solution was washed with water (1.5 L), dried overmagnesium sulfate then concentrated under vacuum to provide 227 g ofethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate as a white solid m.p.98-100° C.

Part D

Potassium ethoxide (173.5 g) was added in portions with stirring to amixture of ethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate (227 g) andN,N-dimethylformamide (1.6 L). The reaction mixture was cooled with anice bath to control the resulting exotherm. The reaction mixture wasstirred overnight at ambient temperature then quenched with water (17L). The pH was adjusted to pH with acetic acid (170 mL). The resultingprecipitate was isolated by filtration, rinsed with water thenreslurried with water (2.5 L). The solid was isolated by filtration,rinsed with water then oven dried (55 to 60° C.) for 16 hours to provide169.0 g of a white solid. A 3.0 g sample was recrystallized fromethanol/dichloromethane to provide tetrazolo[1,5-a]quinolin-5-ol as awhite solid, m.p. 248° C. (dec.). Analysis: Calculated for C₉H₆N₄O: % C,58.06; % H, 3.25; % N, 30.09; Found: % C, 58.02; % H, 3.29; % N, 30.20.

EXAMPLE 2 4-Nitrotetrazolo[1,5-a]quinolin-5-ol Hydrate

Tetrazolo[1,5-a]quinolin-5-ol (10 g, 54 mmole, Example 1) was suspendedin acetic acid (200 mL) then warmed to 40° C. Nitric acid (4 mL of 16M,59 mmole) was added to the reaction mixture. The reaction mixture washeated at 80° C. for 30 minutes then allowed to cool to ambienttemperature. The resulting precipitate was isolated by filtration,rinsed with water then recrystallized from isopropanol/water to provide8.1 g of 4-nitrotetrazolo[1,5-a]quinolin-5-ol hydrate as light yellowplates, m.p. 186.5-187° C. Analysis: Calculated for C₉H₅N₅O₃·H₂O: % C,43.38; % H, 2.83; % N, 28.10; Found: % C, 43.27; % H, 2.84; % N, 28.25.

EXAMPLE 32-Methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol

Sodium azide (19.5 g, 0.3 moles),2-methyl-[(2-chloro-3-nitroquinolin-4-yl)amino]-2-propanol (29.6 g, 0.10mole, U.S. Pat. No. 4,988,815 Example 12) and N,N-dimethylformamide (100mL) were added to a jacketed 1 liter round bottom flask with the outsideportion containing acetone. The reaction mixture was stirred with astirring bar and the acetone refluxed to provide a constant internalreaction temperature of 53° C. After 18 hours the reaction mixture wasdiluted with water (100 mL). The resulting yellow precipitate wasisolated by filtration then washed with 50% N,N-dimethylformamide/wateruntil the washes became light colored. The yellow/green solid was thenwashed with water, pressed dry and washed with ether. The solid was airdried to provide 27.2 g of crude product as a yellow/light green solid.This material was recrystallized from ethanol/dichloromethane to provide2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol as ayellow crystalline solid, m.p. 204° C. (dec.). Analysis: Calculated for:C₁₃H₁₄N₆O₃: % C, 51.65; % H, 4.67; % N, 27.8; Found: % C, 51.30; % H,4.69; % N, 27.43.

EXAMPLE 4[(4-Amino-5-tetrazolo[1,5-c]quinolinyl)amino]-2-methyl-2-propanol

2-Methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol (30.2g, 0.10 mole, Example 3), ethanol (300 mL) and 5% Pd/C (1.0 g of 50%water wet) were placed in a Paar apparatus. The mixture washydrogenated. The mixture was diluted with dichloromethane then filteredto remove the catalyst. The filtrate was concentrated under vacuum. Thecrude product was recrystallized from ethanol to provide 20.5 g of[(4-amino-5-tetrazolo[1,5-c]quinolinyl)amino]-2-methyl-2-propanol as ayellow/green crystalline solid, m.p. 164-167° C. Analysis: Calculatedfor C₁₃H₁₆N₆O: % C, 57.33; % H, 5.92; % N, 30.88; Found: % C, 56.94; %H, 5.88; % N, 30.80.

EXAMPLE 5α,α-Dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol

[(4-Amino-5-tetrazolo[1,5-c]quinolinyl)amino]-2-methyl-2-propanol (5 g,0.18 mole, Example 4) was dissolved in triethyl orthoformate (17 g). Thesolution was heated at 120° C. for 20 hours. The reaction mixture wasallowed to cool to ambient temperature then it was diluted with 1 Nhydrochloric acid. Formic acid (20 mL) was added to the mixture whichwas then heated at reflux for an hour. The reaction mixture wasconcentrated under vacuum then neutralized with sodium hydroxide. Thecrude product was recrystallized from ethanol/ethyl acetate to provideα,α-dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol as asolid, m.p. 245-248° C. Analysis: Calculated for C₁₄H₁₄N₆O: % C, 59.55;% H, 4.99; % N, 29.77; Found: % C, 59.44; % H, 4.93; % N, 29.65.

EXAMPLE 6α,α5-Trimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol

Acetyl chloride (16 g, 0.020 mole) was added dropwise to a solution of[(4-amino-5-tetrazolo[1,5-c]quinolinyl)amino]-2-methyl-2-propanol (5 g,0.18 mole, Example 4) in acetonitrile. The reaction mixture was stirredat ambient temperature for 4 hours. The resulting precipitate wasisolated by filtration then dissolved in acetic acid (about 50 mL). Thissolution was refluxed for 2 hours then neutralized with carbonate. Thecrude product was isolated by filtration then recrystallized initiallyfrom hexane/ethyl acetate then from ethanol/ethyl acetate to provideα,α,5-trimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol asa solid, m.p. 202-205° C. Analysis: Calculated for C₁₅H₁₆N₆O: % C, 60.8;% H, 5.44; % N, 28.36; Found: % C, 60.68; % H, 5.48; % N, 28.28.

EXAMPLE 7 4-Hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline

4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (10.0 g, 0.0385moles, U.S. Pat. No. 4,689,338 Example 77) was added to hydrazine (30mL). The mixture heated rapidly to reflux. The solid dissolved with avigorous heat of reaction then a precipitate formed as the reactionmixture refluxed. The reaction mixture was diluted with water. Theprecipitate was isolated by filtration then suspended in water (100 mL).The solid was brought into solution by the addition of acetic acid. Thesolution was filtered to remove traces of undissolved solid. Thefiltrate was made basic by the addition of ammonium hydroxide. Theresulting precipitate was isolated by filtration, washed with water thendried to provide 8.0 g of crude product as a white solid. A sample ofthis material was recrystallized from methanol to provide4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 202-205°C. Analysis: Calculated for C₁₄H₁₇N₅: % C, 65.86; % H, 6.71; % N, 27.43;Found: % C, 65.20; % H, 6.6; % N, 27.5.

EXAMPLE 8 6-(2-Methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline

A solution of sodium nitrite (2.0 g, 3 mmole) in water (5 mL) was addedto a solution of4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (4.0 g, 15.7mmole, Example 7) in a mixture of acetic acid (5 mL) and water (50 mL).The reaction mixture was stirred at ambient temperature for 15 minutes.A precipitate was isolated by filtration, washed with water then airdried to provide 4.1 g of crude product. This material wasrecrystallized from dichloromethane/ethanol to provide 3.0 g of6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a creamcolored crystalline solid, m.p. 208-212° C. Analysis: Calculated forC₁₄H₁₄N₆: % C, 63.14; % H, 5.30; % N, 31.56; Found: % C, 62.60; % H,5.2; % N, 31.5.

EXAMPLE 9α,α-Dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol

A suspension of4-chloro-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (1.0 g, 3.6mmole, U.S. Pat. No. 4,689,338 Example 189 Part D) in hydrazine (3 mL,6.9 mmole) was heated on a steam bath for 1 hour then diluted withwater. The resulting precipitate was isolated by filtration. The solidwas dissolved in a mixture of acetic acid (2 mL) and water (15 mL) thencombined with a solution of sodium nitrite (0.5 g) in water. Theresulting precipitate was isolated by filtration, washed with water anddried to provide 0.71 g ofα,α-dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol as awhite solid, m.p. 246-247° C. (shrunk at 230° C.). Analysis: Calculatedfor C₁₄H₁₄N₆O: % C, 59.56; % H, 5.00; % N, 29.77; Found: % C, 59.45; %H, 5.06; % N, 29.51.

EXAMPLE 101-(2-Methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine

6-(2-Methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline (0.2 g,0.75 mmole, Example 8), triphenylphosphine (0.4 g, 1.5 mmole) and1,2-dichlorobenzene (5 mL) were combined and heated at reflux overnight.The reaction mixture was concentrated under vacuum then diluted withcyclohexane (25 mL). The resulting precipitate was isolated byfiltration, washed with cyclohexane then dried to provide1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amineas a solid, m.p. 209-210° C. Analysis: Calculated for C₃₂H₂₉N₄P: % C,76.78; % H, 5.84; % N, 11.19; Found: % C, 76.03; % H, 5.87; % N, 11.09.

EXAMPLE 11 4-Amino-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

Triphenylphosphine (4.5 g, 17.0 mmole) was added to a mixture ofα,α-dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol (2.4g, 8.5 mmole, Example 9) and 1,2-dichlorobenzene. The reaction mixturewas heated at reflux for 3 hrs then concentrated under vacuum. Theresidue was combined with methanol (400 mL) and hydrochloric acid (50 mLof 0.5N) then heated on a steam bath for 2 hours. The resultingprecipitate was isolated by filtration then washed with ether. The solidwas dissolved in water and the solution was made basic with 10% sodiumhydroxide. After stirring for 30 minutes, the reaction mixture wasfiltered. The collected solid was rinsed with water and ether thenrecrystallized from N,N-dimethylformamide/ethanol to provide about 1 gof 4-amino-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol as a solid,m.p. 271-273° C. Analysis: Calculated for C₁₄H₁₆N₄O: % C, 65.6; % H,6.29; % N, 21.86; Found: % C, 65.37; % H, 6.26; % N, 21.61.

EXAMPLE 12 1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

1-(2-Methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine(100 mg, Example 10) was suspended in a mixture of methanol (3 mL) andhydrochloric acid (10 mL of 0.5N). The mixture was heated on a steambath for 2 hours then allowed to stand at ambient temperature overnight.The reaction mixture was filtered. The filtrate was made basic with 10%sodium hydroxide. The resulting precipitate was isolated by filtrationthen dried to provide1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. The spectralproperties of this material matched those of an authentic sample.

EXAMPLE 13 4-Nitrotetrazolo[1,5-a]quinolin-5-ol

Aqueous sodium hydroxide (30 g of 50%) was added to a suspension of2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol (34.0g, 0.1125 mole, Example 3) in water (500 mL). The mixture was heated ona steam bath and the solid dissolved rapidly. The solution was heatedfor about 30 minutes and then upon stirring a solid began toprecipitate. The mixture was made acidic with 6N hydrochloric acid. Theresulting solid was isolated by filtration; washed in succession withwater, ethanol and ether; then dried under vacuum at 100° C. to provide23.2 g of crude product as a pale yellow/green solid. A sample (3.2 g)was recrystallized initially from methanol/dichloromethane and then fromtoluene to provide 4-nitrotetrazolo[1,5-a]quinolin-5-ol. Analysis:Calculated for C₉H₅N₅O₃: % C, 46.76; % H, 2.18; % N, 30.29; Found: % C,46.85; % H, 2.23; % N, 29.91.

EXAMPLE 144-Nitrotetrazolo[1,5-a]quinolin-5-yl]trifluoromethanesulfonate

Triethylamine (0.6 mL, 4.32 mmole) was added to a suspension of4-nitrotetrazolo[1,5-a]quinolin-5-ol (1.0 g, 4.32 mmoles, Example 2) indichloromethane (20 mL). The reaction mixture was cooled to 0° C.Triflic anhydride (0.73 mL, 4.32 mmole) was added. The reaction mixturewas stirred for 3 hours at 0° C. The reaction mixture was diluted withdichloromethane (50 mL), washed with 0.5 N hydrochloric acid, dried overmagnesium sulfate and concentrated under vacuum. The residue wascombined with hexanes (100 mL), refluxed for 15 minutes and filtered. Asolid precipitated from the filtrate on cooling. The solid was isolatedby filtration and dried to provide 0.2 g of4-nitrotetrazolo[1,5-a]quinolin-5-yl]trifluoromethanesulfonate as awhite solid, m.p. 132-134° C. Analysis: Calculated for C₁₀H₁₄F₃N₅O₅S: %C, 33.07; % H, 1.11; % N, 19.28; Found: % C, 33.19; % H, 1.28; % N,19.61.

EXAMPLE 15 N-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine

Isobutylamine (1 mL) was added to a solution of4-nitrotetrazolo[1,5-a]quinolin-5-yl]trifluoromethanesulfonate (0.5 g,1.37 mmole, Example 14) in dichloromethane (50 mL). The reaction mixturewas stirred at ambient temperature for 4 hours, diluted withdichloromethane (50 mL), washed with water (2×50 mL), dried overmagnesium sulfate then concentrated under vacuum. The residue waspurified by filtering through a layer of silica gel eluting with 2%methanol in dichloromethane. The resulting yellow solid wasrecrystallized from ethyl acetate to provide 0.31 g ofN-(2-methylpropyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine, m.p.152-154° C. Analysis: Calculated for C₁₃H₁₄N₆O₂: % C, 54.54; % H, 4.93;% N, 29.35; Found: % C, 54.45; % H, 4.73; % N, 29.47.

EXAMPLE 16 N⁵-(2-Methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine

N-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine (1.0 g, 3.5mmole, Example 15), ethanol (100 mL) and Pt/C were placed in a Paarapparatus. The mixture was hydrogenated at 50 psi (3.44×10⁵ Pa). Thereaction mixture was filtered to remove the catalyst then concentratedunder vacuum. The residue was recrystallized from ethyl acetate toprovide 0.35 g ofN⁵-(2-methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine as off whiteneedles, m.p. 148-150° C. Analysis: Calculated for C₁₃H₁₆N₆: % C, 60.92;% H, 6.29; % N, 32.79; Found: % C, 60.94; % H, 6.25; % N, 32.93.

EXAMPLE 17 6-(2-Methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline

N⁵-(2-Methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine (0.2 g, 0.78mmole, Example 16) was combined with diethoxymethyl acetate (2 mL) andheated on a steam bath for 3 hours. Water (10 mL) and 10% sodiumhydroxide (2 mL) were added and the reaction mixture was heated on asteam bath for 1 hour. A solid was isolated by filtration thenrecrystallized from methanol/ethyl acetate to provide 0.16 g of6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a whitecrystalline solid, m.p. 210-212° C. Analysis: Calculated for C₁₄H₁₄N₆: %C, 63.14; % H, 5.30; % N, 31.56; Found: % C, 63.12; % H, 5.32; % N,31.61.

EXAMPLE 18 N-(1,1-Dimethylethyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine

Triethylamine (6 mL), 4-nitrotetrazolo[1,5-a]quinolin-5-ol (8.7 g, 37.6mmole, Example 13) and dichloromethane (100 mL) were combined andstirred at ambient temperature until a solution was obtained. Thesolution was cooled to −15° C. Triflic anhydride (6.5 mL) was added inportions to the cooled solution. The reaction mixture was allowed towarm to ambient temperature then filtered through a layer of silica gel.The filtrate was washed with cold dilute hydrochloric acid then driedover magnesium sulfate. Triethylamine (5.25 mL) was added to thedichloromethane solution and the resulting mixture was stirred for about10 minutes. tert-Butylamine (4.2 mL) was added dropwise to the reactionmixture. The reaction mixture was heated on a steam bath for about 15minutes. The resulting solid was isolated by filtration then purified bysilica gel chromatography to provide the crude product as a yellowsolid. This material was recrystallized from ethanol/water to provide 5g of N-(1,1-dimethylethyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine. Thestructure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 19 N⁵-(1,1-Dimethylethyl)tetrazolo[1,5-a]quinoline-4,5-diamine

N-(1,1-dimethylethyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine (4.2 g,Example 18), ethanol (100 mL) and Pt/C (0.5 g) were placed in a Paarapparatus. The mixture was hydrogenated. The reaction mixture wasfiltered to remove catalyst then concentrated to dryness under vacuum.The residue was recrystallized from ethyl acetate/dichloromethane toprovide N⁵-(1,1-dimethylethyl)tetrazolo[1,5-a]quinoline-4,5-diamine as apale blue crystalline solid.

EXAMPLE 206-(1,1-Dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline

Diethoxymethyl acetate (1.9 mL) was added dropwise to a solution ofN⁵-(1,1-dimethylethyl)tetrazolo[1,5-a]quinoline-4,5-diamine (1.5 g, 5.9mmole, Example 19) in acetic acid (15 mL). The reaction mixture washeated on a steam bath for 1 hour then made basic with sodium hydroxide.The resulting precipitate was isolated by filtration then recrystallizedfrom ethanol to provide6-(1,1-dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline, m.p.224-226° C. Analysis: Calculated for C₁₄H₁₄N₆: % C, 63.13; % H, 5.29; %N, 31.56; Found: % C, 62.90; % H, 5.44; % N, 31.52.

EXAMPLE 21 6H-Imidazo[4,5-c]tetrazolo[1,5-a]quinoline

6-(1,1-Dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline (1 g,3.8 mmole, Example 20) was added to hydrochloric acid (5 mL of 6N);water (20 mL) was added and the mixture was heated on a steam bath for 1hour. The reaction mixture was allowed to cool to ambient temperaturethen made basic (pH 11) by the addition of sodium hydroxide solution.The resulting precipitate was isolated by filtration, dried thenrecrystallized from N,N-dimethylformamide to provide 0.65 g of thedesired product as a solid. A sample of this material was refluxed in alarge amount of dichloromethane/methanol, isolated by filtration, thendried to provide 6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a solid,m.p. >300° C. Analysis: Calculated for C₁₀H₆N₆: % C, 57.14; % H, 2.88; %N, 39.98; Found: % C, 56.89; % H, 3.10; % N 39.34. The structure wasconfirmed by both mass spectroscopy and nuclear magnetic resonancespectroscopy.

1-35. (canceled)
 36. A compound according to claim 32 wherein R₁ ishydrogen, and R₂ is hydrogen. 37-42. (canceled)